Stereocomplementary Routes to Hydroxylated Nitrogen Heterocycles: Total Syntheses of Casuarine, Australine, and 7‐epi‐Australine

Abstract

Addition of lithiated 1-benzyloxyallene to a D-arabinose-derived cyclic nitrone occurred with perfect diastereoselectivity furnishing a bicyclic 1,2-oxazine derivative, which is an excellent precursor for pyrrolizidine alkaloids hydroxylated at C-7 with optional configuration at this stereogenic center. Depending on the stage of the N-O bond cleavage and ring re-closure, 7-hydroxypyrrolizidines with 7R or 7S configuration were obtained, as a result of completely selective addition reactions occurring complementarily at the bottom or top face of the endocyclic C-C double bond in six- and five-membered B rings, respectively. Applicability of these stereodivergent routes to obtain polyhydroxy pyrrolizidine alkaloids is demonstrated by the efficient syntheses of casuarine and australine as examples of the two classes of diversely configured 7-hydroxypyrrolizidine alkaloids. An alternative synthesis of australine and two strategies for the preparation of 7-epi-australine are also reported, which demonstrate that the stereoselectivity of hydride reduction of an exocyclic C-O double bond is independent of the ring size, occurring preferentially from the top face either in a six- or five-membered ring.

Human Acid β‐Glucosidase Inhibition by Carbohydrate Derived Iminosugars: Towards New Pharmacological Chaperones for Gaucher Disease

“…Pyrrolizidine iminosugars 40-55 and 64-68 (Schemes 7, 8, and 10) weres elected from ap anel synthesized in our laboratories.H yacinthacine A 2 (40,S cheme 7), casuarine (41), and (À)-uniflorine A( 42)a re natural products; [35][36][37] all have the darabino configuration at one of the two five-membered rings of the pyrrolizidinen ucleus. [38] Compounds 40-51 (Scheme 7) were synthesized from 4 either by nitrone cycloadditionc hemistry, [39] ap owerful strategy that allows the stereoselective installation of up to three stereocenters not present in the starting sugar, [40] or by the lithio allene addition strategy.…”

“…[38] Compounds 40-51 (Scheme 7) were synthesized from 4 either by nitrone cycloadditionc hemistry, [39] ap owerful strategy that allows the stereoselective installation of up to three stereocenters not present in the starting sugar, [40] or by the lithio allene addition strategy. [41] These approaches also allowed the synthesis of the unnatural derivatives7 -deoxyuniflorine (46), [42] pyrrolizidine 47, [43] and the two glucosyl pyrrolizidines 50 [44] and 51. [39c] Pyrrolizidines 52-55 (Scheme 8), which have the d-ribo configuration at one of the two five-membered rings of the pyrro- ChemBioChem 2015, 16,2054 -2064 www.chembiochem.org lizidine nucleus, were synthesized from 10 by nitrone cycloaddition chemistry.…”

Direct synthesis of imino-C-nucleoside analogues and other biologically active iminosugars

“…Figure 5 highlights the further application of this convenient strategy to the rapid preparation of several structurally complex polyhydroxy indolizidine and pyrrolizidine alkaloids, including analogues of the glycosidase inhibitors hyacinthacine and steviamine. While several strategies could be exploited for the second annulation event, ready access to the N -allyl pyrrolidine 40 , alkyl chloride 33 and protected ketones 34 and 35 suggested annulation events involving ring closing metathesis 38 39 , alkylation 24 40 41 or reductive amination 17 42 . For example, heating the dienylpyrrolidine 40 with the Hoveyda–Grubbs 2nd generation catalyst 43 in toluene provided the unsaturated indolizidine 45 in excellent overall yield from 4-pentenal ( 44 ).…”

Reactions of Lithiated Methoxyallene with Oxime Derivatives - Formation of 1,2-Oxazines and Functionalized Isoxazole Derivatives

“…Subsequent, often spontaneous cyclizations lead to a variety of heterocycles such as furan, thiophene, pyrrole, piperidine, pyridine and oxazole derivatives. The additions of 1 to a broad range of simple or complex nitrones 2 offer an excellent direct access to 1,2‐oxazine derivatives 3 (Scheme ) that are versatile intermediates for the stereoselective preparation of natural products and their analogs or of carbohydrate mimetics . This smooth addition of lithiated alkoxyallenes 1 to nitrones 2 initiated a brief exploratory study of related compounds, containing N−O bonds, electrophiles such as oximes, nitrile oxides or nitrosoalkenes to further broaden the scope of alkoxyallene reactivity.…”